Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis

Dazhi Xu, Chien Feng Li, Xian Zhang, Zhaohui Gong, Chia Hsin Chan, Szu Wei Lee, Guoxiang Jin, Abdol Hossein Rezaeian, Fei Han, Jing Wang, Wei Lei Yang, Zi Zhen Feng, Wei Chen, Ching Yuan Wu, Ying Jan Wang, Lu Ping Chow, Xiao Feng Zhu, Yi Xin Zeng, Hui Kuan Lin

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Abstract

Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.

Original languageEnglish
Article number6641
JournalNature communications
Volume6
DOIs
Publication statusPublished - 2015 Mar

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Xu, D., Li, C. F., Zhang, X., Gong, Z., Chan, C. H., Lee, S. W., Jin, G., Rezaeian, A. H., Han, F., Wang, J., Yang, W. L., Feng, Z. Z., Chen, W., Wu, C. Y., Wang, Y. J., Chow, L. P., Zhu, X. F., Zeng, Y. X., & Lin, H. K. (2015). Skp2-MacroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. Nature communications, 6, [6641]. https://doi.org/10.1038/ncomms7641